A process for preparing an angiotensin converting enzyme inhibitor. Phosphorus pentachloride is reacted with the carboxylic acid group of an amino acid to form an acyl chloride hydrochloride. The resulting hydrochloride salt is then coupled with a silylated amino acid in a non-aqueous medium to form a high yield peptide. The peptide is used as an angiotensin converting enzyme (ACE) inhibitor.
|
10. A process for preparing a compound of the formula (I): ##STR12## wherein R1 represents ##STR13## R2 represents C1 -C6 alkyl; R3 represents C1 -C6 alkyl, phenyl or phenylmethyl;
R4 represents phenyl(C1 -C6)alkyl, phenyl or C1 -C6 alkyl; and A represents amino acid residue;
comprising reacting a compound of formula (II): ##STR14## wherein R1 and R2 are defined as above; with a silylated amino acid in a non-aqueous medium. 1. A process for preparing a compound of the formula (I): ##STR6## wherein R1 represents ##STR7## R2 represents C1 -C6 alkyl; R3 represents C1 -C6 alkyl, phenyl or phenylmethyl;
R4 represents phenyl(C1 -C6)alkyl, phenyl or C1 -C6 alkyl; and A represents amino acid residue;
comprising the following steps: (a) reacting a compound of formula (III): ##STR8## wherein R1 and R2 are defined as above; with phosphorus pentachloride to obtain a compound of formula (II): ##STR9## wherein R1 and R2 are defined as above; and (b) reacting the compound of formula (II) with a silylated amino acid in a non-aqueous medium. 2. The process as claimed in
4. The process as claimed in
5. The method as claimed in
6. The method as claimed in
7. The method as claimed in
8. The method as claimed in
9. The method as claimed in
11. The process as claimed in
13. The process as claimed in
14. The method as claimed in
15. The process as claimed in
16. The process as claimed in
17. The process as claimed in
18. The process as claimed in
|
|||||||||||||||||||||||||||||||||
1. Field of the Invention
The present invention relates to a process for preparing an angiotension converting enzyme (ACE) inhibitor, and in particular to a process for preparing angiotension converting enzyme inhibitors such as intermediates of captopril, enalapril, quinapril and the like without using phosgene, diphosgene and triphosgene.
2. Description of the Related Arts
The synthesis of enalapril, an angiotensin coverting enzyme inhibitor which is used among other things in the treatment of blood pressure, by coupling amino acids has been disclosed in many patents. For example, in European Patent No. 0215335, enalaprils are prepared by reacting N-[(s-ethoxycarbonyl-3-phenyl-propyl]-L-alanine with phosgene to form N-carboxylanhydride, followed by condensation with L-proline. This process uses noxious phosgene.
U.S. Pat. No. 5,359,086 discloses a process for the preparation of enalapril. According to the process, alkyl-L-alanine is reacted with a coupling agent, N,N-carbonyldiimidazole to form alkyl-L-alanine-N-carboxy anhydride. The alkyl-L-alanine-N-carboxy anhydride is then coupled with L-proline silyl ester hydrochloride to form the enalapril. The coupling agent, N,N-carbonyldiimidazole, is expensive.
In Spain Patent No. 544781, a process for preparing enalapril has been proposed. The process involves reacting alkyl-L-alanine with N-hydroxysuccinimide and dicyclohexylcarbodiimide (DCC) to form N'-succinimidyl ester and coupling the N'-succinimidyl ester with L-proline. However, it is hard to remove DCC.
U.S. Pat. No. 4,808,741 discloses a process for preparing pharmaceutically active carboxylalkyl dipeptides such as enalapril, lisinopril and the like. In the process, the amino acid group of a L-proline is protected with a benzyl protecting group. Subsequently, the protecting group is removed.
It is therefore an object of the invention to provide a safe process for preparing angiotensin converting enzyme inhibitors such as enalapril, quinapril, delapril and ramipril by avoiding the use of noxious phosgene, diphosgene and triphosgene.
The object of the invention is achieved by using a non-expensive and safe coupling agent, phosphorus pentachloride. It is found that the phosphorus pentachloride can activate the carboxylic acid group of an amino acid to form acyl chloride and, in the mean time, protect the amino group, thereby leading to the formation of a hydrochloride salt. The resulting hydrochloride salt can be coupled further with a silylated amino acid in a non-aqueous medium to form peptide. When using this process to synthesize enalapril, the yield can be as high as 96%.
Generally, the process of the invention can be used to prepare an ACE inhibitor of the following formula (I): ##STR1## wherein R1 represents ##STR2## R2 represents C1 -C6 alkyl; R3 represents C1 -C6 alkyl, phenyl or phenylmethyl;
R4 represents phenyl(C1 -C6)alkyl, phenyl or C1 -C6 alkyl; and
A represents amino acid residue.
According to the process, the compound of formula (III): ##STR3## wherein R1 and R2 are defined as above, is first activated by phosphorus pentachloride in a non-aqueous medium at a temperature of -10°C-0°C to form a hydrochloride salt of acyl chloride of formula (II): ##STR4##
The compound II is then subjected to condensation with a silylated amino acid in a non-aqueous medium at a temperature of -10°C-0° C. When the condensation reaction is complete, water is added to stop the reaction. After extraction with an organic solvent such as dichloromethane or ethyl acetate, drying and concentration, ACE inhibitors of compound I can be obtained in high yield.
The group of non-aqueous mediums suitable for use in the invention includes but is not limited to acetone, acetonitrile, dioxan, methylene chloride and tetrahydrofuran.
The silylated amino acid can be silylated proline, the derivatives thereof, or silylated 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The silylated amino acid is prepared by reacting an amino acid with hexamethylsilazane (HMDS), chlorotrimethylsilane and bis(trimethylsilyl)acetamide (BSA).
In the preparation of enalapril, N-[1(S)-ethoxycarbonyl-3-peheylporopyl]-L-alanine (compound III, wherein R1 is ##STR5## R2 is methyl, R3 is ethyl and R4 is phenylethyl) is reacted with phosphorus pentachloride, followed by condensation with a silylated proline. The acyl chloride of the L-alanine can be coupled with other amino acids using phosphorus pentachloride as a coupling agent to form various ACE inhibitors such as quinapril, imidapril, ramipril and spirapril.
The following examples are intended to demonstrate the invention more fully without acting as a limitation upon its scope, since numerous modifications and variations will be apparent to those skilled in this art.
PAC Synthesis of N-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-L-proline1 g (3.6 mmole) of (2S)-2-[N-1-(ethoxycarbonyl)-2-benzoyl]ethyl amino propionate was added to a reaction flask containing 1.27 g(6 mmole) of phosphorus pentachloride and 3 ml of methylene chloride by using a solid addition funnel, and agitated at 0°C for 6 hours. 6 ml of heptane was then added, and a white solid precipitated. The resulting suspension was filtrated and the cake was washed with heptane giving N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine acid chloride.
L-proline, in the amount of 0.48 g(4.0 mmol), bis(trimethylsilyl)acetamide (BSA), in the amount of 1 ml (4.0 mmol), and 4 ml of methylene chloride were placed in a 25 ml three-neck reaction flask. The reaction mixture was then agitated at room temperature until the solution became clear. 0.5 ml (3.6 mmol) of triethylamine was then added and the temperature was lowered to -10°C 4 ml of methylene chloride and the L-alanine acid chloride were then mixed and dropped into the reaction flask and agitated at -10°C for 30 minutes. 6 ml of water was then added to stop the reaction. 3M hydrochloric acid was then added to the resulting solution to adjust the pH to about 3. After extracting with methylene chloride(10 ml×3) and drying over magnesium sulfate and concentrating by a vacuum concentrator, 1.26 g (3.43 mmol) of the title compound was obtained as a colorless liquid in a 96% yield.
1.26 g of the obtained title compound and 0.34 g (2.9 mmol) of maleic acid were heated and dissolved in 10 ml of ethyl acetate. After standing at room temperature for 7 hours, filtering and drying, 0.86 g of the salt of the title compound was obtained.
1 HNMR(400 MHz, CD3 OD): δ7.18-7.31 (m,5H), 6.25(s,2H), 4.51(dm, 1H), 4.26-4.34(m,2H), 4.23(dq,1H), 3.89(dt,1H), 3.54-3.68 (m,2H), 2.70-2.86(m,2H), 2.19-2.36(m,4H), 1.98-2.07(m,2H),1.54(dd,3H), 1.32(t,3H).
PAC Synthesis of N-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-L-proline5 ml of methylene chloride was added to a reaction flask containing 1.27 g (6 mmol) of phosphorus pentachloride. The temperature was then lowered to -10°C and 1 g (3.6 mmol) of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine was added using a solid addition funnel. The reaction solution was then allowed to react at 0°C for 5 hours. 8 ml of heptane was added and stirred for 30 minutes. The solid obtained after filtration was dissolved in 10 ml of methylene chloride.
6 ml of methylene chloride and 0.97 ml (7.6 mmol) of chlorotrimethyl silane were added to a separate reaction flask containing 0.48 g (4 mmol) of L-proline. The reaction mixture was allowed to react for 1.5 hours at room temperature and then 1.54 ml(11 mmol) of triethylamine was added and the temperature was lowered to -10°C The L-alanine acid chloride was then added into the reaction flask and stirred at 0°C for 1 hour. 10 ml of water was then added and stirred. After extracting with methylene chloride, drying and concentrating, the title compound was obtained in a 76.4% yield. The NMR spectra data was the same as that obtained in Example 1.
PAC Synthesis of N-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-L-proline5 ml of methylene chloride was added to a reaction flask containing 1.27 g (6 mmol) of phosphorus pentachloride. The temperature was then lowered to -10°C and 1 g (3.6 mmol) of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine was added using a solid addition funnel. The reaction solution was then allowed to react at 0°C for 5 hours. 8 ml of heptane was added and stirred for 30 minutes. The solid obtained after filtration was dissolved in 10 ml of methylene chloride.
4 ml of methylene chloride and 0.86 ml (4.1 mmol) of hexamethyldisilazane, HMDS) were added to a separate reaction flask containing 0.48 g (4 mmol) of L-proline. The reaction mixture was refluxed for 30 minutes and then lowered to room temperature. 0.52 ml(3.7 mmol) of triethylamine was then added and the temperature was lowered again to -10°C The L-alanine acid chloride was then added into the reaction flask and stirred at 0°C for 1 hour. 10 ml of water was then added and stirred. After extracting with methylene chloride, drying and concentrating, the title compound was obtained in a 79.4% yield. The NMR spectra data was the same as that obtained in Example 1.
PAC Synthesis of quinapril5 ml of methylene chloride was added to a reaction flask containing 1.27 g (6 mmol) of phosphorus pentachloride. The temperature was then lowered to 0°C and 1 g (3.6 mmol) of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine was added using a solid addition funnel. The reaction solution was then allowed to react at room temperature for 4 hours. 8 ml of heptane was added and stirred for 30 minutes. The solid obtained after filtration was dissolved in 10 ml of methylene chloride.
4 ml of methylene chloride and 2 ml (8 mmol) of BSA were added to a separate reaction flask containing 0.74 g (4.2 mmol) of (S)-(-)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The reaction mixture was allowed to react at room temperature for 2 hours. 0.52 ml(3.7 mmol) of triethylamine was then added and the temperature was lowered to 0°C The L-alanine acid chloride was then added into the reaction flask and stirred at room temperature overnight. 10 ml of water was then added and stirred. After extracting with methylene chloride, drying and concentrating, the title compound was obtained in a 83.9% yield.
1 HNMR (400 MHz, CD3 OD): δ7.14-7.30 (m, 9H), 4.13-4.24 (m,2H), 3.90-4.02 (m,2H), 3.61(dt, 1H), 3.20(q,2H),2.87-2.96(m,2H), 2.44-2.71(m, 2H), 1.59-1.67(m,2H), 1.50(d,3H, 1.25(t,3H. MS(m/e): 439(M+1).
PAC Synthesis of (S)-1-(3-acetylthio-2-methyl-oxopropyl)-L-proline5 ml of methylene chloride was added to a reaction flask containing 1.27 g (6 mmol) of phosphorus pentachloride. The temperature was then lowered to 0°C and 0.58 g (3.6 mmol) of (S)-3-acetylthio-2-methyl propanic acid was added using a solid addition funnel. The reaction solution was then allowed to react at room temperature for 5 hours. The solvent was evaporated and 10 ml of heptane was added to the residue.
4 ml of methylene chloride and 1 ml (4 mmol) of BSA were added to a separate reaction flask containing 0.48 g (4 mmol) of L-proline. The reaction mixture was allowed to react at room temperature for 1 hour. 0.52 ml(3.7 mmol) of triethylamine was then added and the temperature was lowered to 0°C The methylene chloride solution was then added into the reaction flask and stirred at room temperature overnight. 10 ml of water was then added and stirred After extracting with methylene chloride, drying and concentrating, the title compound was obtained in a 77.9% yield.
1 HNMR(200 MHz, CDCl3): δ 10.57 (s,1H), 4.34 (dt, 1H), 3.5-3.6 (m, 2H), 3.06-3.12 (m, 2H), 2.6-2.9 (dq, 1H), 2.27(s,3H), 1.96-2.15(m, 4H), 1.21(d, 3H). MS(m/e): 260(M+1).
Tsai, Hui-Ping, Wang, Shin-Shin
| Patent | Priority | Assignee | Title |
| 5977380, | Feb 17 1999 | Everlight USA, Inc. | Process for preparing N-[1- (S)-ethoxycarbonyl-3- phenylpropyl]-L-alanine derivatives |
| 6541635, | Mar 29 2002 | Everlight USA, Inc. | Method for producing angiotensin converting enzyme inhibitor |
| 7022677, | Feb 18 1999 | KAKEN PHARMACEUTICAL CO , LTD ; Molecular Research Institute | Amide derivatives as growth hormone secretagogues |
| Patent | Priority | Assignee | Title |
| 4808741, | Dec 29 1986 | TORCAN CHEMICAL LTD , A CORP OF ONTARIO | Process for preparing carboxyalkyl dipeptides |
| 5359086, | Sep 16 1992 | KRKA, PHARMACEUTICAL AND CHEMICAL WORKS | Process for preparing alkyl-L-alanyl-L-proline derivatives |
| Executed on | Assignor | Assignee | Conveyance | Frame | Reel | Doc |
| Jun 23 1998 | WANG, SHIN-SHIN | Industrial Technology Research Institute | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 009295 | /0217 | |
| Jun 23 1998 | TSAI, HUI-PING | Industrial Technology Research Institute | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 009295 | /0217 | |
| Jun 29 1998 | Industrial Technology Research Institute | (assignment on the face of the patent) | / |
| Date | Maintenance Fee Events |
| Aug 08 2002 | M183: Payment of Maintenance Fee, 4th Year, Large Entity. |
| Aug 28 2002 | REM: Maintenance Fee Reminder Mailed. |
| Aug 09 2006 | M1552: Payment of Maintenance Fee, 8th Year, Large Entity. |
| Sep 13 2010 | REM: Maintenance Fee Reminder Mailed. |
| Feb 09 2011 | EXP: Patent Expired for Failure to Pay Maintenance Fees. |
| Date | Maintenance Schedule |
| Feb 09 2002 | 4 years fee payment window open |
| Aug 09 2002 | 6 months grace period start (w surcharge) |
| Feb 09 2003 | patent expiry (for year 4) |
| Feb 09 2005 | 2 years to revive unintentionally abandoned end. (for year 4) |
| Feb 09 2006 | 8 years fee payment window open |
| Aug 09 2006 | 6 months grace period start (w surcharge) |
| Feb 09 2007 | patent expiry (for year 8) |
| Feb 09 2009 | 2 years to revive unintentionally abandoned end. (for year 8) |
| Feb 09 2010 | 12 years fee payment window open |
| Aug 09 2010 | 6 months grace period start (w surcharge) |
| Feb 09 2011 | patent expiry (for year 12) |
| Feb 09 2013 | 2 years to revive unintentionally abandoned end. (for year 12) |